Systemic lupus erythematosus (SLE) is a devastating autoimmune disease marked by the production of autoantibodies, anti-Smith (Sm) being the most specific for the disease. The etiology of SLE is known to have significant genetic and environmental components. Abundant data link deficiencies of the complement system to the development of autoimmune diseases, particularly SLE. Deficiencies of either complement protein C4 or the complement receptor CR2 (CD21) trigger development of SLE-like disease in mice. Partial or complete C4 deficiency strongly predisposes to SLE in humans, and recently, decreased CD21 expression has been observed in human SLE patients. How these genetic deficiencies in complement interact with environmental effectors to trigger disease is unknown. We have crossed mice deficient for C4 or CD21 to a transgenic line which expresses an Ig heavy-chain specific for Sm. We propose to study the effect of environmental stressors on anti-Sm B cells and the development of anti-Sm antibodies in these mice to elucidate the interplay between genetic and environmental components of SLE development. [unreadable] [unreadable]